CN116087389A - HPLC determination method of bivalirudin related substances for injection - Google Patents
HPLC determination method of bivalirudin related substances for injection Download PDFInfo
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- CN116087389A CN116087389A CN202211699028.XA CN202211699028A CN116087389A CN 116087389 A CN116087389 A CN 116087389A CN 202211699028 A CN202211699028 A CN 202211699028A CN 116087389 A CN116087389 A CN 116087389A
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- 108010055460 bivalirudin Proteins 0.000 title claims abstract description 40
- 229960001500 bivalirudin Drugs 0.000 title claims abstract description 40
- OIRCOABEOLEUMC-GEJPAHFPSA-N bivalirudin Chemical compound C([C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)CNC(=O)CNC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 OIRCOABEOLEUMC-GEJPAHFPSA-N 0.000 title claims abstract description 40
- 238000000034 method Methods 0.000 title claims abstract description 32
- 238000002347 injection Methods 0.000 title claims abstract description 26
- 239000007924 injection Substances 0.000 title claims abstract description 26
- 239000000126 substance Substances 0.000 title claims abstract description 24
- 238000004128 high performance liquid chromatography Methods 0.000 title claims abstract description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 18
- 239000005695 Ammonium acetate Substances 0.000 claims description 18
- 229940043376 ammonium acetate Drugs 0.000 claims description 18
- 235000019257 ammonium acetate Nutrition 0.000 claims description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 16
- 238000001514 detection method Methods 0.000 claims description 16
- 239000000243 solution Substances 0.000 claims description 14
- 239000000523 sample Substances 0.000 claims description 13
- 239000012488 sample solution Substances 0.000 claims description 11
- 229960000583 acetic acid Drugs 0.000 claims description 8
- 239000007853 buffer solution Substances 0.000 claims description 8
- 239000012362 glacial acetic acid Substances 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 6
- 238000010828 elution Methods 0.000 claims description 5
- 238000001228 spectrum Methods 0.000 claims description 5
- 239000011259 mixed solution Substances 0.000 claims description 4
- 238000004587 chromatography analysis Methods 0.000 claims description 2
- 238000007865 diluting Methods 0.000 claims description 2
- 239000008215 water for injection Substances 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 108090000765 processed proteins & peptides Proteins 0.000 abstract description 3
- 239000007974 sodium acetate buffer Substances 0.000 abstract description 2
- 238000000825 ultraviolet detection Methods 0.000 abstract description 2
- 238000004458 analytical method Methods 0.000 description 6
- 239000000872 buffer Substances 0.000 description 5
- 108090000190 Thrombin Proteins 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 229960004072 thrombin Drugs 0.000 description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- 230000010100 anticoagulation Effects 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000001632 sodium acetate Substances 0.000 description 3
- 235000017281 sodium acetate Nutrition 0.000 description 3
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 229940127219 anticoagulant drug Drugs 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 241000122205 Chamaeleonidae Species 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 108010007267 Hirudins Proteins 0.000 description 1
- 102000007625 Hirudins Human genes 0.000 description 1
- 208000007814 Unstable Angina Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 239000000337 buffer salt Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 229940006607 hirudin Drugs 0.000 description 1
- WQPDUTSPKFMPDP-OUMQNGNKSA-N hirudin Chemical group C([C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(OS(O)(=O)=O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H]1NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H]2CSSC[C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@H](C(NCC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N2)=O)CSSC1)C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C)[C@@H](C)O)CSSC1)C(C)C)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 WQPDUTSPKFMPDP-OUMQNGNKSA-N 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000013037 reversible inhibitor Substances 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000001732 thrombotic effect Effects 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/34—Control of physical parameters of the fluid carrier of fluid composition, e.g. gradient
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/62—Detectors specially adapted therefor
- G01N30/74—Optical detectors
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- Physics & Mathematics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Spectroscopy & Molecular Physics (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Abstract
The invention discloses an HPLC determination method of bivalirudin related substances for injection, belonging to the technical field of peptide compound determination. The method uses sodium acetate buffer solution-acetonitrile as a mobile phase, and uses a main component self-contrast method to determine relevant substances of bivalirudin for injection under the condition of proper ultraviolet detection wavelength and flow rate. The method can well separate related substances to achieve baseline, and can accurately determine the content of the related substances of bivalirudin for injection. The method is simple, quick, accurate, efficient and good in reproducibility, and establishes a good foundation for the establishment of the bivalirudin quality standard for injection.
Description
Technical Field
The invention relates to an HPLC determination method of bivalirudin related substances for injection, belonging to the technical field of peptide compound determination.
Background
Bivalirudin (Bivalirudin), which is a novel synthetic anticoagulant drug, is a direct, specific and reversible inhibitor of thrombin. Was originally developed successfully by the company barji (Biogen) switzerland, later assigned to the united states medicare company, approved for sale in the united states in 2000. The anticoagulant component is a hirudin-derived 20 peptide compound. Whether thrombin in the blood circulation or thrombotic-bound chemical book thrombin, bivalirudin can specifically bind to its catalytic site and anion binding site, thereby directly inhibiting thrombin activity, and its action is characterized by transiently reversible. Early clinical studies showed that: the bivalirudin anticoagulation treatment effect is definite, the incidence rate of bleeding is low, and compared with the traditional heparin anticoagulation treatment, the bivalirudin anticoagulation treatment effect is safer to use. Is mainly used for preventing ischemic complications before and after the unstable angina pectoris of the vascular shaping interventional therapy.
In the determination of bivalirudin related substances for injection, common impurities have the following structural formula:
at present, no HPLC detection method of bivalirudin related substances for injection is reported and literature data exist.
Therefore, the development of a simple and feasible method for eluting and separating bivalirudin and several impurities existing in bivalirudin in sequence and performing quantitative analysis is imperative and has important significance.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide an HPLC (high Performance liquid chromatography) measuring method for measuring bivalirudin related substances for injection. The method utilizes the high performance liquid chromatography of gradient elution to realize effective elution, separation and quantitative injection of related substances in bivalirudin, so that the related substances are completely separated from a main peak, the analysis speed is high, and the detection effect is good.
In order to achieve the above purpose, the invention adopts the following technical scheme:
an HPLC determination method of bivalirudin related substances for injection, wherein the chemical structural formula of the bivalirudin related substances is as follows:
the HPLC determination method comprises the following steps:
(1) Preparation of the sample solution to be tested
Preparation of i solution: preparing bivalirudin water for injection into a solution with the concentration of 2mg/ml, obtaining a map through chromatographic analysis, analyzing the map, and obtaining the peak area of bivalirudin in a sample through analyzing a sample solution;
ii, solution preparation: diluting the solution i with water to obtain a control solution with the concentration of 20 mug/ml;
(2) Sample detection
Adopting a C18 chromatographic column, wherein a mobile phase consists of a mobile phase A and a mobile phase B, wherein the mobile phase A is a mixed solution of an ammonium acetate buffer solution and water, and the volume fraction of the water is 30% -70%; the concentration of the ammonium acetate buffer solution in the mobile phase A is 0.01mol/L to 0.2mol/L, and the pH value is adjusted to 3.0 to 7.0 by glacial acetic acid; the mobile phase B is a mixed solution of an ammonium acetate buffer solution and acetonitrile, wherein the volume fraction of the acetonitrile is 30% -70%.
The gradient elution time to mobile phase ratio is as follows:
the flow rate is 0.7-1.5 ml/min, the detection wavelength is 205 nm-254 nm, the column temperature is 30-60 ℃, the sample solution i and the sample solution ii which are prepared in the step (1) and are to be detected are respectively injected into HPLC, the spectrum is obtained after detection, and the content of the bivalirudin related substances in the sample is obtained through a self-contrast method.
The preferred technical scheme of the invention is as follows:
1. the detection wavelength adopted by the invention is 205 nm-254 nm, wherein when the detection wavelength is 226nm, the ultraviolet absorption intensity is moderate, so the detection wavelength is preferably 226nm.
2. The pH of the buffer salt solution adopted by the invention is adjusted to 3.0-7.0 by glacial acetic acid, and when the pH value is 5.8, the separation degree is highest, so the pH value is selected to be 5.8.
3. In mobile phase a of the process of the invention, the volume fraction of water is 50%.
4. In the mobile phase B of the method, the volume fraction of acetonitrile is 30% -70%, and the volume fraction of acetonitrile is 40%, so that the analysis time can be minimized and the analysis efficiency can be improved by using the mobile phase with the volume fraction of acetonitrile of 40% for sample testing on the premise of ensuring that baseline separation is achieved.
5. Further, the concentration of the ammonium acetate buffer in the step (2) is 0.05mol/L.
6. Further, the flow rate of the mobile phase in the step (2) is 1ml/min.
7. Further, the column temperature in the step (2) is 30 ℃.
8. The optimal technical scheme of the invention is as follows:
HPLC instrument: race mer U3000;
chromatographic column: vydac C18, 4.6X250 mm,5 μm;
mobile phase: taking 0.05mol/L ammonium acetate buffer solution (taking 3.9g of ammonium acetate, adding 1000ml of water for dissolution, adjusting the pH value to 5.8 by glacial acetic acid) -water (1:1) as a mobile phase A, and taking 0.05mol/L sodium acetate buffer solution-acetonitrile (1:1) as a mobile phase B;
detection wavelength: 226nm;
flow rate: 1ml/min;
column temperature: 30 ℃.
Compared with the prior art, the invention has the following beneficial effects:
the method can effectively analyze bivalirudin for injection: the method uses ammonium acetate buffer solution-acetonitrile as a mobile phase, and uses a main component self-contrast method to determine relevant substances of bivalirudin for injection under the condition of proper ultraviolet detection wavelength and flow rate. The method can well separate related substances to achieve baseline, and can accurately determine the content of the bivalirudin related substances. The method is simple, quick, accurate, efficient and good in reproducibility, and establishes a good foundation for the establishment of the bivalirudin quality standard for injection.
Drawings
FIG. 1A chromatogram of a 1.1ml/min flow rate system applicability solution in example 1 of the present invention;
FIG. 2 is a chromatogram of a 42℃column temperature system applicability solution in example 2 of the present invention;
FIG. 3 is a chromatogram of a solution of the invention for a system applicability at column temperature of 30℃in example 3.
Detailed Description
The present invention will be further illustrated by the following specific examples, but the scope of the present invention is not limited to the following examples.
The instruments and medicines used in the following examples were as follows:
the HPLC instrument is a Siemens U3000, an ultraviolet detector, a chameleon chromatographic workstation, a chromatographic column of Vydac C18, 4.6X250 mm,5 μm, an electronic analytical balance (Sidoris, one ten thousandth), an ultrapure water system (Mirabo), bivalirudin for injection, bivalirudin reference substance, ammonium acetate and acetonitrile.
Example 1
And taking a proper amount of bivalirudin for injection, and preparing 2mg/ml bivalirudin test sample solution for injection by using water.
Vydac C18, 4.6X108 mm,5 μm column, 0.05mol/L ammonium acetate buffer (3.9 g ammonium acetate, 1000ml water was added to dissolve, pH adjusted to 5.8 with glacial acetic acid) -water (1:1) as mobile phase A, and 0.05mol/L sodium acetate buffer-acetonitrile (1:1) as mobile phase B were used. The detection wavelength is 226nm, the flow rate is 1.1ml/min, the sample injection amount is 20 μl, and the column temperature is 30 ℃. The analysis spectrum of the obtained sample is shown in figure 1.
Example 2
And taking a proper amount of bivalirudin for injection, and preparing 2mg/ml bivalirudin test sample solution for injection by using water.
Vydac C18, 4.6X108 mm,5 μm column, 0.05mol/L ammonium acetate buffer (3.9 g ammonium acetate, 1000ml water was added to dissolve, pH adjusted to 5.8 with glacial acetic acid) -water (1:1) as mobile phase A, and 0.05mol/L sodium acetate buffer-acetonitrile (1:1) as mobile phase B were used. The detection wavelength is 226nm, the flow rate is 1.0ml/min, the sample injection amount is 20 μl, and the column temperature is 42 ℃. The analysis spectrum of the obtained sample is shown in figure 2.
Example 3
And taking a proper amount of bivalirudin for injection, and preparing 2mg/ml bivalirudin test sample solution for injection by using water. Vydac C18, 4.6X108 mm,5 μm column, 0.05mol/L ammonium acetate buffer (3.9 g ammonium acetate, 1000ml water was added to dissolve, pH adjusted to 5.8 with glacial acetic acid) -water (1:1) as mobile phase A, and 0.05mol/L sodium acetate buffer-acetonitrile (1:1) as mobile phase B were used. The detection wavelength is 226nm, the flow rate is 1.0ml/min, the sample injection amount is 20 μl, and the column temperature is 30 ℃. The analysis spectrum of the obtained sample is shown in figure 3.
Claims (9)
1. A method for HPLC determination of bivalirudin related substance for injection, characterized by: the chemical structural formula of the bivalirudin related substance is as follows:
the HPLC determination method comprises the following steps:
(1) Preparation of the sample solution to be tested
Preparation of i solution: preparing bivalirudin water for injection into a solution with the concentration of 2mg/ml, obtaining a map through chromatographic analysis, analyzing the map, and obtaining the peak area of bivalirudin in a sample through analyzing a sample solution;
ii, solution preparation: diluting the solution i with water to obtain a control solution with the concentration of 20 mug/ml;
(2) Sample detection
Adopting a C18 chromatographic column, wherein a mobile phase consists of a mobile phase A and a mobile phase B, wherein the mobile phase A is a mixed solution of an ammonium acetate buffer solution and water, and the volume fraction of the water is 30% -70%; the concentration of the ammonium acetate buffer solution in the mobile phase A is 0.01mol/L to 0.2mol/L, and the pH value is adjusted to 3.0 to 7.0 by glacial acetic acid; the mobile phase B is a mixed solution of an ammonium acetate buffer solution and acetonitrile, wherein the volume fraction of the acetonitrile is 30% -70%.
The gradient elution time to mobile phase ratio is as follows:
the flow rate is 0.7-1.5 ml/min, the detection wavelength is 205 nm-254 nm, the column temperature is 30-60 ℃, the sample solution i and the sample solution ii which are prepared in the step (1) and are to be detected are respectively injected into HPLC, the spectrum is obtained after detection, and the content of the bivalirudin related substances in the sample is obtained through a self-contrast method.
2. The method according to claim 1, characterized in that: the concentration of the ammonium acetate buffer solution is 0.05mol/L.
3. The method according to claim 1, characterized in that: the pH of the mobile phase A is adjusted to 5.8 by glacial acetic acid.
4. The method according to claim 1, characterized in that: the volume fraction of water in the mobile phase A in the step (2) is 50%.
5. The method according to claim 1, characterized in that: the volume fraction of acetonitrile in the mobile phase B in the step (2) is 40%.
6. The method according to claim 1, characterized in that: the ratio of the gradient elution time of the mobile phase to the mobile phase in the step (2) is as follows:
7. the method according to claim 1, characterized in that: the flow rate of the mobile phase in the step (2) is 1.0ml/min.
8. The method according to claim 1, characterized in that: the detection wavelength in the step (2) is 226nm.
9. The method according to claim 1, characterized in that: the column temperature in the step (2) is 30 ℃.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070093423A1 (en) * | 2005-09-14 | 2007-04-26 | Avi Tovi | Process for production of Bivalirudin |
| WO2011071799A2 (en) * | 2009-12-11 | 2011-06-16 | Dr. Reddy's Laboratories Ltd. | Purification of bivalirudin |
| CN110187036A (en) * | 2019-07-02 | 2019-08-30 | 昆明龙津药业股份有限公司 | A kind of method of quality control of Angiomax raw material and its preparation |
| CN110208419A (en) * | 2019-06-26 | 2019-09-06 | 海南中和药业股份有限公司 | It is a kind of for detecting the analysis method of impurity in bivalirudin |
-
2022
- 2022-12-28 CN CN202211699028.XA patent/CN116087389B/en active Active
Patent Citations (4)
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| US20070093423A1 (en) * | 2005-09-14 | 2007-04-26 | Avi Tovi | Process for production of Bivalirudin |
| WO2011071799A2 (en) * | 2009-12-11 | 2011-06-16 | Dr. Reddy's Laboratories Ltd. | Purification of bivalirudin |
| CN110208419A (en) * | 2019-06-26 | 2019-09-06 | 海南中和药业股份有限公司 | It is a kind of for detecting the analysis method of impurity in bivalirudin |
| CN110187036A (en) * | 2019-07-02 | 2019-08-30 | 昆明龙津药业股份有限公司 | A kind of method of quality control of Angiomax raw material and its preparation |
Non-Patent Citations (4)
| Title |
|---|
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